Bicyclic diketopiperazines

In another approach, 2,7,8-trisubstituted bicyclic diketopiperazine libraries were synthesized starting from piper-azinecarboxylic acid <2000TL4841, 2001W02001/046197>. 

A bicyclic diketopiperazine 159 as a potential peptide (3-tum mimetic was developed via solid-supported synthesis [51]. The Ugi reaction among the resin... 

The scope and limitations of the solid-supported symthesis of bicyclic diketopi-perazines 165 as peptide p-tum mimetic were further investigated by Golebiowski et al. [52]. The four-component Ugi reaction of a-iV-Boc-diaminopropionic acid resin ester 160 (an amine input) and optically active a-bromoacid 163 with various isocyanides 166 and aldehydes 167 yields a series of bicyclic diketopiperazines 165 (Scheme 28). 

Scheme 26 Synthesis of bicyclic diketopiperazines and two representative 3D conformations of...

Further applications for the preparation of jfi-turn mimetics have also been reported by Martens et al. with the synthesis of pipecolic acid derivatives 88 (presumably proceeding via a cyclic Schiff base - not a true post-condensation modification ) [74] and Golebiowski and co-workers who have reported the solid-supported synthesis of bicyclic diketopiperazines with the generic structure 89, via the multi-step synthesis shown in Scheme 11.18 [75]. 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Bicydomycin (aizumycin). C,2H,gN207, Mr 302.28, cryst., mp. 187-189°C (decomp.), [ajo +63.5° (CH3OH), water-soluble, bicyclic diketopiperazine antibiotic produced by Streptomyces sapporonensis and S. aizjunensis with in vitro and in vivo activity... 

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Gilley CB, Kobayashi Y (2008) 2-nitrophenyl isocyanide as a versatile convertible isocyanide rapid access to a fused y-lactam (3-lactone bicycle. J Org Chem 73 4198 204 Chen JJ, Golebiowski A, Klopfenstein SR, West L (2002) The universal Rink-isonitrile resin applications in Ugi reactions. Tetrahedron Lett 43 4083 085 Hulme C, Peng J, Morton G, Salvino JM, Herpin T, Labaudiniere R (1998) Novel safety-catch linker and its application with a Ugi/De-BOC/Cyclization (UDC) strategy to access carboxylic acids, 1, 4-benzodiazepines, diketopiperazines, ketopiperazines and dihydroqui-noxalinones. Tetrahedron Lett 39 7227-7230... 

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

A diketopiperazine 8 with an external guanidine function is proven to be an effective catalyst for the Strecker reaction of benzhydrylimine [14]. Corey s bicyclic guandine 20 [12b], which is the original of 12 (Scheme 4.12), also works well in the same reaction and the mode of action has been elucidated by density functional theory [63] (Scheme 4.22). 

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